title: Synthesis and structure-activity relationship studies of 3-substituted indolin-2-ones as effective neuroprotective agents.
abstract: Neurodegenerative diseases are a major health problem particularly among the elderly. Drugs to prevent or slow down the death of neurons are urgently needed but are currently unavailable. We previously reported that the c-Raf inhibitor, GW5074 {5-iodo-3-[(3',5'-dibromo-4'-hydroxyphenyl) methylene]-2-indolinone}, is protective in tissue culture and in vivo paradigms of neurodegeneration. However, at doses slightly higher than those at which it is protective, GW5074 displays toxicity when tested in neuronal cultures. We report herein the synthesis, biological evaluation, and structure-activity relationship (SAR) studies of novel 3-substituted indolin-2-one compounds that are highly neuroprotective but lack the toxicity of GW5074. Of the 45 analogs tested in this study, compounds 7, 37, 39, and 45 were found to be the most potent neuroprotective and thus represent promising lead compounds for preclinical development for the treatment of neurodegenerative disorders.
authors.affiliation: Dept. of Molecular and Cell Biology, University of Texas, Richardson, TX 75083, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Balderamos
authors.forename: Haribabu
authors.initials: H
authors.lastname: Ankati
authors.forename: Shashidhar Kumar
authors.initials: SK
authors.lastname: Akubathini
authors.forename: Anish V
authors.initials: AV
authors.lastname: Patel
authors.forename: Sukanta
authors.initials: S
authors.lastname: Kamila
authors.forename: Chandrani
authors.initials: C
authors.lastname: Mukherjee
authors.forename: Lulu
authors.initials: L
authors.lastname: Wang
authors.forename: Edward R
authors.initials: ER
authors.lastname: Biehl
authors.forename: Santosh R
authors.initials: SR
authors.lastname: D'Mello
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D009410:Nerve Degeneration / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D018696:Neuroprotective Agents